There is considerable evidence that excess adiposity is a risk factor for post-menopausal breast cancer, however the exact mechanism for this association is not known. While it has been hypothesized that the increase is the result of endogenous production of estrogen in adipose tissue, our understanding of the complex mechanism for this association is quite limited. Since the estrogen receptor plays a key role in mediating the biological impact of estrogen, inherited variants in the estrogen receptor-alpha {ESR1) gene are important candidates to study the association of estrogen, adiposity, and breast cancer risk. We propose a genetic/genomic epidemiology approach to test the central hypothesis that breast cancer risk is modulated by underlying single nucleotide and copy number variation in the ESR1 gene, and that excess adiposity modifies the association. We will conduct a genetic association study to evaluate the association of ESR1 genetic variation (single nucleotide and copy number variation) and breast cancer risk, and analyze the potential modifying effect of adiposity. We will also examine the association of ESR1 variants and adiposity with tumor characteristics, and investigate whether adiposity is related to differences in ESR1 copy number between germline DNA and breast cancer tumor DNA samples. The main objectives of the Career Development Award include gaining experience in the genetic epidemiology of breast cancer, becoming an expert in the characteristics and measurement of copy number variation in the genome and how to integrate the study of this newly recognized type of genetic variation into epidemiologic studies, while simultaneously conducting specific hypothesis-driven analyses. The specific aims will be accomplished using an existing case-control study of breast cancer in Western New York. The applicant, who is a trained epidemiologist, will utilize the skills attained during her postdoctoral training in genetic epidemiology to become an expert in cancer biology with a focus on the contributions of estrogen and adiposity, evaluation of different types of genomic variation and the relation with cancer and will obtain further training in cancer genetics/genomics. RELEVANCE: The increasing prevalence of adiposity in the U.S. and the consistent relationship of adiposity and post- menopausal breast cancer warrant further study of how adiposity, estrogen, and breast cancer are related. The proposal is significant because we will shed light on the complex interaction of estrogen, adiposity, and breast cancer.